Abstract
Myeloid derived suppressor cells (MDSCs) from tumor-bearing mice are important negative regulators of anti-cancer immune responses, but the role for immature myeloid cells (IMCs) in non-tumor-bearing mice in the regulation of immune responses are poorly described. We studied the immune-suppressive activity of IMCs from the bone marrow (BM) of C57Bl/6 mice and the mechanism(s) by which they inhibit T–cell activation and proliferation. IMCs, isolated from BM by high-speed FACS, inhibited mitogen-induced proliferation of CD4+ and CD8+ T-cells in vitro. Cell-to-cell contact of T-cells with viable IMCs was required for suppression. Neither neutralizing antibodies to TGFβ1, nor genetic disruption of indolamine 2,3-dioxygenase, abrogated IMC-mediated suppressive activity. In contrast, suppression of T-cell proliferation was absent in cultures containing IMCs from interferon-γ (IFN-γ) receptor KO mice or T-cells from IFN-γ KO mice (on the C57Bl/6 background). The addition of NO inhibitors to co-cultures of T-cells and IMC significantly reduced the suppressive activity of IMCs. IFN-γ signaling between T-cells and IMCs induced paracrine Nitric Oxide (NO) release in culture, and the degree of inhibition of T-cell proliferation was proportional to NO levels. The suppressive activity of IMCs from the bone marrow of tumor-free mice was comparable with MDSCs from BALB/c bearing mice 4T1 mammary tumors. These results indicate that IMCs have a role in regulating T-cell activation and proliferation in the BM microenvironment.
Highlights
Normal bone marrow (BM) contains a heterogeneous population of cells, including immature macrophages, granulocytes, and myeloid dendritic cells
Carboxyfluorescein diacetate succinimidyl diester (CFSE) divided Tcells from control bead-activated cultures had more than 5-fold higher Ki-67 expression compared with CFSE divided T-cells that had been co-cultured with CD11b+ GR-1+ immature myeloid cells (IMCs) sorted cells, indicating that IMC suppress both T-cell activation and cell division (Fig. S2)
In contrast to previous studies that suggested BM-derived CD11b+GR-1+ IMCs from tumor-free mice lack immunosuppressive activity [8], this is the first study to definitively document that CD11b+GR-1+ IMCs isolated from the BM of non tumor-bearing mice have comparable ability to suppress T-cell proliferation as Myeloid derived suppressor cells (MDSCs) from tumor-bearing mice
Summary
Normal BM contains a heterogeneous population of cells, including immature macrophages, granulocytes, and myeloid dendritic cells. Immature myeloid cells, termed myeloid-derived suppressor cells (MDSC), are expanded in tumor-bearing mice, and in patients with cancer, trauma, and autoimmunity [1,2]. While an immunosuppressive role of tumor-associated MDSCs has been well characterized in murine models [8], the immunomodulatory functions of BM-derived CD11b+GR-1+ IMCs from normal mice has not been well studied. A number of reports have described natural suppressor (NS) myeloid cells in BM from non-tumor bearing animals [11,12], most studies during the last 20 years have focused on tumor-associated myeloid-derived suppressor cells and suggest that BM-derived CD11b+ GR-1+ immature myeloid cells (IMCs) in normal, tumor-free mice lack immunosuppressive activity [8,13]
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